Mulberry Diels–Alder-type adducts: isolation, structure, bioactivity, and synthesis

Mulberry Diels–Alder-type adducts (MDAAs) are unique phenolic natural products biosynthetically derived from the intermolecular [4 + 2]-cycloaddition of dienophiles (mainly chalcones) and dehydroprenylphenol dienes, which are exclusively distributed in moraceous plants. A total of 166 MDAAs with diverse skeletons have been isolated and identified since 1980. Structurally, the classic MDAAs characterized by the chalcone-skeleton dienophiles can be divided into eight groups (Types A − H), while others with non-chalcone dienophiles or some variations of classic MDAAs are non-classic MDAAs (Type I). These compounds have attracted significant attention of natural products and synthetic chemists due to their complex architectures, remarkable biological activities, and synthetic challenges. The present review provides a comprehensive summary of the structural properties, bioactivities, and syntheses of MDAAs. Cited references were collected between 1980 and 2021 from the SciFinder, Web of Science, and China National Knowledge Internet (CNKI). Graphical Abstract


Introduction to mulberry Diels-Alder-type adducts (MDAAs)
Mulberry Diels-Alder-type adducts (MDAAs), characteristic constituents of mulberry trees (Morus plants of the family Moraceae), are a group of structurally unique natural phenolic compounds biosynthetically derived from the intermolecular [4 + 2]-cycloaddition of dienophiles (mainly chalcones) and dehydroprenylphenol dienes (Scheme 1). Chalcomoracin . and kuwanons G and H (albanins F and G), the first representatives of MDAAs, were almost simultaneously reported from the well-known mulberry tree (Morus alba L.) by the two groups of Nomura and Takasugi in 1980 [1][2][3][4][5]. A total of 166 MDAAs have been obtained and characterized over the past four decades. MDAAs are not widely distributed in the plants of the family Moraceae, and until now, they have only found in seven genera (

Structural characteristics and classification of MDAAs
According to the structural characteristics, MDAAs can be divided into classic and non-classic types. Structurally, classic MDAAs share the same chalcone-skeleton dienophiles but differ in the dehydroprenylphenol dienes.
In light of the structural types of dehydroprenylphenol dienes, classic MDAAs ( Fig. 1) can be further classified into dehydroprenyl-2-arylbenzofuran type (Type A), dehydroprenylstilbene type (Type B), dehydroprenylchalcone type (Type C), dehydroprenylflavone type (Type D), dehydroprenyldihydroflavone type (Type E), dehydroprenylsanggenonflavone type (Type F), dehydroprenylcoumarin type (Type G), and simple or other dehydroprenylphenol type (Type H). Non-classic MDAAs (Type I) is considered as a kind of Diels-Alder adducts derived from cycloaddition of non-chalcone dienophiles and dehydroprenylphenol dienes or as variations of some classic MDAAs. All MDAAs are phenolic natural products, and the presence of adjacent phenolic hydroxyl groups has allowed different natural modifications of the ketone as well as of newly formed methylcyclohexene ring, resulting in compounds with complex structural features. In addition, the presence of intact or modified prenyl groups in the moiety of dienophiles or dienes also leads to a diversity of MDAAs. The occurrence and distribution details of 166 MDAAs together with their specific rotation values are summarized in Table 1.
As shown in the biosynthetic pathway of classic MDAAs (Scheme 1), a new methylcyclohexene ring with three chiral carbons (C-3", C-4", and C-5") was produced in the Diels-Alder cycloaddition of the chalcone dienophile and the dehydroprenylphenol diene, in which the relative configuration of H-4" and H-5" would always maintain the original trans configuration while the stereochemistry of H-3" and H-4" would have cis and trans configurations. Therefore, this kind of Diels-Alder product has trans-trans and cis-trans types, both of which are found in natural products. From the structural characteristics of endo-and exo-adducts in the Diels-Alder reaction, the trans-trans type adducts have been found to be exo-addition products, while the cis-trans type adducts are attributed to endo-addition. According to the current data statistics, the ratio of the reported natural MDAAs with trans-trans and cis-trans types is about 1:1.5. It is noteworthy that natural MDAAs seem to be formed in the manner of in vitro [4 + 2] cycloaddition reactions.
The trans-trans and cis-trans types of classic MDAAs could be easily determined by analysis of the coupling constant of H-4" with H-3" and H-5" (generally, large J 3"/4" and J 4"/5" for trans-trans; small J 3"/4" and large J 4"/5" for cis-trans:) in the 1 H NMR spectrum with resolvable signals. Sometimes this kind of compound usually exists as an equilibrium mixture of conformational isomers in solution, which requires NMR variable

Scheme 1 The biosynthesis pathway of classic MDAAs
Page 4 of 63 Luo et al. Natural Products and Bioprospecting (2022) 12:31 temperature experiments to obtain the resolvable signals of the methylcyclohexene ring [17,22,74,85,94,110,118,124]. Based on X-ray crystallographic analysis and circular dichroism (CD) spectroscopic evidence, in 1988 the Nomura group proposed the empirical rules for determining the absolute configuration of the chiral centers on the methylcyclohexene ring in classic MDAAs [12]: a) the stereochemistry of C-3", C-4", and C-5" in the trans-trans type MDAAs was 3"R,4"R,5"S, while in the cis-trans type MDAAs was 3"S,4"R,5"S. b) The transtrans type MDAAs exhibited negative optical rotations, and their Cotton effect at the maximum UV absorption tended to be negative, while the cis-trans type MDAAs showed the opposite optical rotations and Cotton effect. More reports of natural and synthetic MDAAs with clear absolute structures established by single crystals analysis, chemical methods, or ECD calculation methods have confirmed the practicability of Nomura's empirical rules. In this review, all MDAAs with clear relative configurations have determined their absolute configurations according to the empirical rules.
Compounds 24 − 30 [16,19,25,46,[56][57][58], a series of type A-I MDAAs with a 6-membered oxygen ring similar to 23, which primarily differed in their methylcyclohexene ring and C-8″ carbon as well as the prenyl substituent. The appearance of the double bond (Δ 2″ ) on the methylcyclohexene ring made the C-3" chirality of these compounds disappear, while the absolute configuration of other chiral carbons remained unchanged. Morusalbin A (27) [46] featured with an additional furan ring formed by cyclization between C-2" and C-5′ through an oxygen atom, which could structurally derive from mongolicin C (24) [25]. Mulberrofuran I (28) [56] and mulberrofurans S and Q (29 and 30) [57,58] were first detected in M. bombycis and M. alba, respectively, which could also be regarded as the 4H-pyran derivatives of 24. Similarly, with 24 as the precursor, its 3′ or 5′-OH condensed with C-8" ketone to form a hemiketal intermediate, which was dehydrated to yield 28 and further oxidized to 6"-hydroxylated product 29 or the epoxy derivative 30. The orientations of 5-OH in 29 and the epoxy ring in 30 were not yet determined.   [23,25,29,39,40,46,50,51,54,64,[78][79][80]. All ketalized MDAAs were reported as cis-trans configuration based on the coupling constants of H-4" with H-3" and H-5" (small J 3"/4" and large J 4"/5" ). The relative configuration of the new chiral carbon C-8" of this class of ketalized MDAAs could be determined by the NOE correlations of 8"-Ar-H with methylcyclohexene ring protons, and then its absolute configuration could be assigned bases on the empirical rules. Albanol A (mulberrofuran G, 31) was first isolated from M. alba bark by Rama Rao et al. in 1983, and its absolute configuration was confirmed by X-ray analysis of its pentamethyl ether [63]. In 1984, mulberrofuran F (32) and mulberrofuran G (31) were found from the root barks of M. lhou by Fukai et al. and mulberrofuran G was identified as albanol A by comparison of their NMR and physical data [64]. While the absolute configuration of 32 was determined by the Nomura group in 1988 [12]. In addition, compound 32 was also obtained in the above-mentioned conversion of 7 to 18 [22]. Mongolicin A (34), the only ketalized MDAAs possessing a prenyl unit in the moiety of diene, which was isolated from the stem and root bark of M. mongolica [25]. Morusalisin B (37) without analysis of the relative configuration of C-8″ was discovered from cell cultures of M. alba, and the stereochemistry of C-22″ was not defined [51]. Morusalbin B (42) being characteristic of a 4-membered oxygen ring were purified from the root bark of M. alba [46]. Yunanensin D (43), possessing the hydroxylated methyl and conjugated double bond on cyclohexene ring, was isolated from M. yunanensis [78]. If the cyclohexene ring with conjugated double bond continues to dehydrogenate, an aromatic ring will be obtained, as exemplified by compounds 44 − 49 [40,46,50,79,80]. Sorocenols C and D (47 and 48) were obtained from the root bark of Sorocea bonplandii, which were racemic mixtures due to their zero optical rations [40]. Compared with albanol B (46) [50], the specific optical rotation values of yunanensin A (44) [79] and mulberrofuran P (45) [80] are relatively small (Table 1), and they may also be racemic mixtures in which the ratio of (8"R)-44 or 45 was greater than its (8"S)-enantiomer. Morusalbin C (49), the first non-ketalized MDAAs with an aromatic ring instead of cyclohexene ring, was recently identified from M. alba [46].

Dehydroprenylstilbene type MDAAs (Type B)
A total of 19 MDAAs (Fig. 5, 58 − 76) with dehydroprenylstilbene as the diene have been reported so far. Structurally, most of them (58 − 74) have the original dehydroprenyl group at the para-position of ring A, and only two compounds (75 and 76) at the meta-position of ring A.

Type B with the diene moiety at the meta-position of ring A (Type B-II)
The only two MDAAs of type B-II, guangsangon B (75) [85] and kuwanon P (76) [92], were first obtained from M. macroura and M. lhou. They both possess the transtrans configuration.

Dehydroprenylchalcone type MDAAs (Type C)
There are 15 MDAAs (Fig. 6, 77 − 91) formed by cycloaddition of chalcone dienophile with According to the position of the dehydroprenyl group on chalcone skeleton, type C MDAAs could be divided into the following two subgroups.

Type C with the diene moiety on ring A (Type C-II)
Only one member, namely guangsangon C (91), in this subgroup has been identified so far. As shown in Fig. 6, the position of its dehydroprenyl group is located at C-3 on ring A of the chalcone skeleton, and 91 has the transtrans configuration. Guangsangon C (91) was isolated from the stem bark of M. macroura [85].

Dehydroprenyldihydroflavone type MDAAs (Type E)
Fourteen type E MDAAs have been reported to date, as exemplified by 114 − 127 (Fig. 8), all sharing the dehydroprenyldihydroflavone diene. The location of the dehydroprenyl at dihydroflavone result in two subgroups: type E-I (the diene moiety on ring B) and type E-II (the diene moiety on ring A).

Type E with the diene moiety on ring A (Type E-II)
There are only four compounds in type E-II MDAAs, two (124 and 125) of which feature the C-6 dehydroprenyl and two (126 and 127) feature the C-8 dehydroprenyl. Compounds 124 − 126 are trans-trans configurations, while 127 is cis-trans configuraion. Sanggenon G (124) [121] and sanggenon T (125) [123] have a prenyl group or structure derived thereof at C-7", in which the absolute configurations of C-2 were still not confirmed. Sanggenol M (126) is also characterized by the rare C-7" prenyl, which was isolated from the root barks of M. mongolica [122]. Wittiorumin G (127) obtained from M. wittiorum is the only type E MDAAs with cis-trans configuration [49].

Dehydroprenylsanggenonflavone type MDAAs (Type F)
Sanggenon-type flavanones are a kind of 3-hydroxy-2-prenylflavanones having an ether linkage between C-3 and C-2' , which are characteristic constituents in Morus plants. Sanggenon-type flavanones are very rare in nature, so only several type F MDAAs ( Fig. 9, 128 − 137) derived from sanggenon-type flavanone with the dehydroprenyl group have been reported so far. According to the position of the dehydroprenyl group on sanggenon-type flavanone, type F MDAAs could be divided into the following two subgroups.

Type F with the diene moiety at C-6 of ring B (Type F-I)
Eight members ( Fig. 9 rather than the original structures derived from 2-hydroxy-3-prenylflavanones having an ether linkage between C-3 and C-2' . Except for compounds 130, 131, and 135, the absolute configurations of C-2 and C-3 of 128, 129, and 132 − 134 have not been determined. Sorocein C (134) belonging to the ketalize MDAAs, was isolated from the root bark of S. bonplandii [99]. Cathayanon E (135) has a 6-membered oxygen ring formed by the intramolecular nucleophilic addition of 5-OH with the olefinic C-1", which was obtained from the stem bark of M. cathayana by Zhang et al. in 2009 [91].

Type F with the diene moiety at C-8 of ring B (Type F-II)
Cathayanons A and B (136 and 137) are the only two type F MDAAs with their dehydroprenyl group at C-8 of ring B, which were isolated from M. cathayana by Shen et al. in 2001 [130]. The absolute structure of the cistrans type adduct cathayanon A (136) was confirmed by X-ray crystallographic analysis. The stereochemistry of C-2 and C-3 in the trans-trans type adduct cathayanon B (137) was determined to be the same 2S,3R as compound 136.

Dehydroprenylcoumarin type MDAAs (Type G)
There are only seven members (Fig. 10, 138-144) in this type, in which the dehydroprenyl group is located on its phenyl ring (C-6). All these compounds were isolated from the bark of Brosimum rubescens by Shirota et al. [132], and they share the same cis-trans configuration. The common characteristic of palodesangrens A − E (138 − 142) is the presence of a 6-membered oxygen ring formed by an ether linkage between C-7 and C-8", and the main difference is the number and position of methoxy groups on the chalcone unit. Palodesagretins I and II (143 and 144) [133] have an additional 5-membered ring formed by the carbon bond of C-5 and C-8", and they are different in the position of methoxy groups. The absolute configurations of 138-144 were not determined.

Simple or other dehydroprenylphenol type MDAAs (Type H)
Compounds 145 − 149 ( Fig. 10 [87]. Sanggenon Q (150) [83] from M. mongolica is the only other dehydroprenylphenol type MDAAs, in which the diene is dehydroprenyl-2-oxo-3-prenylisoflavanone and the relative configuration of H-3″, H-4″, and H-5″ is cis-trans. The stereochemistry of its C-3 was not determined.  [25] from M. mongolica are a pair of epimers, in which the dienophile and diene are delivered from the same prenylatedflavone, kuwanon C [33]. Specifically, after Diels-Alder reaction of the C-8 dehydroprenyl group in one molecule and the C-8 prenyl group in another molecule, a further intramolecular cyclodehydrogenation builds a 6-membered oxygen ring in the additions. Dimoracin (153) was isolated from M. alba [136], and its formation process is similar to that of 151 and 152, except that its dienophile and diene are derived from the same prenylated-2-arylbenzofuran, moracin C [136].

Overview on distribution of MDAAs in different plants
MDAAs were at least found in 21 species of the family Moraceae, most of which were isolated and identified from Morus plants (Tables 1 and 2 Table 2). In addition, according to the distribution of MDAAs, this kind of compound could be used as chemotaxonomy biomarker within moraceous plants.

Biological activities
As the characteristic components of Morus plants, MDAAs possess a variety of different biological activities, including antineoplastic, anti-inflammation, antimicrobial, antioxidant, antiviral, anti-neurodegenerative diseases, anti-cardiovascular diseases, as well as PTP1B, α-glucosidase, and tyrosinase inhibitory activities. In this section, we will focus predominantly on the biological and pharmacological activities of natural MDAAs.

Antioxidant activity
MDAAs are phenolic natural products with multiple hydroxyl groups, which contribute their strong antioxidant properties. The Yu and Chen groups evaluated the antioxidant properties of their obtained MDAAs in Fe 2+ / cysteine-induced microsomal lipid peroxidation assay and found that most of the compounds at concentrations of 10 μM had good activities (Vitamine E as the positive control) [17,20,22,25,49,50,74,78,85,91,119,149]. For example, guangsangon J (51), guangsangon I (106), and guangsangon H (121) were first reported to display potent antioxidant activities with the inhibitory rates of malondialdehyde being 91.1%, 93.9%, and 93.1%, respectively, compared to the positive control Vit E (33.4%) [17]. The other active MDAAs were listed in Table 5. In addition, kuwanol E (62) exhibited remarkable free radical scavenging properties with the IC 50 value of 2.1 μg/ mL (the standard trolox, IC 50 = 1.1 μg/mL) [27]. Li et al. found that sanggenon C (130) and sanggenon D (128) may undergo an antioxidant approach to protect mesenchymal stem cells (MSCs) against oxidative stress, and the discrepancies in their antioxidant activities could be attributed to the steric effect [163].

Tyrosinase inhibitory activity
Tyrosinase is a rate-limiting enzyme in the formation of melanin pigments in mammals and the key enzyme for enzymatic browning of many plant-derived food products [170]. Therefore, tyrosinase inhibitors are crucial in the pharmaceutical, skin whitening cosmetic, and food industries. In 2004, Lee et al. first discovered that the natural MDAA sanggenon D (128, IC 50 = 7.3 μM) was a potent tyrosinase inhibitor (the positive control kojic acid, IC 50 = 24.8 μM) [171]. Subsequently, more than 20 MDAAs were reported to have significant inhibitory activity against tyrosinase (Table 8) [19,21,32,36,70,172,173].

Antiviral activity
According to the anti-HBV assay on the HepG 2.2.15 cell line in vitro, mulberrofuran G (31) exhibited moderate inhibitory activity against hepatitis B virus (HBV) DNA replication (IC 50 = 3.99 μM) [66]. At non-toxic concentrations, kuwanon X (58) possessed prominent activities against herpes simplex virus type 1 and 2 (HSV-1 and  HSV-2). The IC 50 values of 58 to the tested strains HSV-1 (15,577), HSV-1 (clinical), and HSV-2 (333) were 2.2, 1.5 and 2.5 μg/mL, respectively. Mechanism studies revealed that 58 could inhibit HSV-1 adsorption and penetration, HSV-1 IE and L genes expression, viral DNA biosynthesis, and the HSV-induced nuclear factor (NF)-κB activation [174]. In the antiviral investigation of Morus spp. plant extracts, the antiviral activity against human coronavirus (HCoV 229E) of their common component kuwanon G (92) was also evaluated [175]. Kuwanon L (118) was found to have the inhibition of HIV-1 integrase (IN) catalytic activity in the absence and in the presence of LEDGF/p75 protein, and could inhibit the IN dimerization, the IN/LEDGF binding, as well as HIV-1 replication [176]. Further study suggested that kuwanon L (118) might exhibit its antiviral activity via binding to multiple viral targets, which may be a promising natural HIV-1 IN inhibitor [177]. Sanggenon G (124) had a certain inhibitory effect on influenza A virus (IC 50 = 30.9 μM) [160].

Other activities
Some MDAAs have also been found as potential inhibitors of disease-related enzymes, such as phosphodiesterase 1 (PDE1) inhibitors [chalcomoracin (5)

Chemical and chemoenzymatic total syntheses of MDAAs
MDAAs exhibit kinds of structurally unique frameworks and a variety of promising bioactivities, and so these natural products have attracted extensive attention from synthetic chemists. Since the first report of total syntheses of several dehydroprenyl-2-arylbenzofuran type (Type A) MDAAs in 2010 [187], an amount of total syntheses of these molecules (including Types A − D and F − G) were disclosed over the past decade. Among all the synthetic strategies for MDAAs, the biomimetic intermolecular [4 + 2]-cycloaddition between a diene and a dienophile is the key step, which might be driven by Lewis acids, organocatalysts, and even enzymes. To the best of our knowledge, there have been no reviews focusing on the total synthesis of these MDAAs until now. In this section, we will cover all chemical and chemoenzymatic total syntheses of the MDAAs and their methyl ether derivatives.

Total syntheses of ( ±)-mulberrofuran J hexamethyl ether, ( ±)-mongolicin F hexamethyl ether, ( ±)-chalcomoracin heptamethyl ether, and ( ±)-mulberrofuran C heptamethyl ether
In 2010, the Rizzacasa group reported firstly the racemic total syntheses of four methyl ether derivatives of dehydroprenyl-2-arylbenzofuran type MDAAs including mulberrofuran J hexamethyl ether (1a), mongolicin F hexamethyl ether (2a), chalcomoracin heptamethyl ether (5a), and mulberrofuran C heptamethyl ether (6a), in which the unit of dehydroprenyl diene was proved to be a challenging intermediate due to its unstable. This diene unit was established by using a Suzuki-Miyaura coupling as the key step, and it was used immediately after rapid purification. They also proved that the presence of the H-bonded phenol in the chalcone dienophile was essential for the success of the [4 + 2]-cycloaddition [187]. As outlined in Scheme 2, the authors started the preparation of the chalcone dienophile S3 from ketone S1 and aldehyde S2 via Claisen-Schmidt condensation. As for the synthesis of dienophile S5, chalcone S3 was prenylated under standard conditions and the resultant prenyl ether S4 was subjected to a Florisil promoted [1,3]-sigmatropic rearrangement to afford the prenylated chalcone S5 in 28% yield. Except for the [1,3]-rearranged product, the corresponding [1, 5]-rearranged isomer (not shown) as well as S3 were also produced in a significant amount.
With the use of Cs 2 CO 3 rather than amine bases, Sonogashira coupling of S8 and phenylalkyne S7, prepared by Seyferth-Gilbert homologation of 4-iodo-3,5-dimethoxybenzaldehyde S6 with Bestman-Ohira reagent, successfully gave the bisphenylalkyne S9 in good yield. After methanolysis of the acetate alkyne S9, the resulting phenol S10 was subsequently subjected to cyclization into the benzofuran S11 in 82% yield using TBAF instead of gold or platinum catalysis. The challenging formation of the dehydroprenyl-2-arylbenzofuran diene S15 was achieved in excellent yield via the Suzuki-Miyaura coupling of iodide S11 and pinacolboronate S14 (preparation by simple hydroboration of enyne S13 with pinacolborane S12) after extensive experimentation.
The intermolecular Diels-Alder cycloaddition reaction between dienophile S3 and diene S15 succeeded to proceed at 180 °C in toluene in a sealed tube to give the exo and endo adducts, trans,trans-1a [the hexamethyl ether derivative of mulberrofuran J (1)] and cis,trans-S16, respectively, in a 1:1 ratio. Cycloaddition of S5 and S15 under the same conditions afforded a 1:2 ratio of the exo adduct mongolicin F hexamethyl ether (2a) and the endo adduct S17. Subsequently, methylation of S16 and S17 obtained the previously reported mulberrofuran C heptamethyl ether (6a) and the permethylation product of chalcomoracin (5), chalcomoracin heptamethyl ether (5a), respectively, which assisted to confirm the stereochemistry of the exo and endo adducts. Unfortunately, the authors did not obtain the natural products mulberrofuran J (1), mongolicin F (2), chalcomoracin (5), and mulberrofuran C (6) by deprotection of either their hexamethyl ether derivatives or heptamethyl ether ones. Claisen-Schmidt condensation of aldehyde S2 and ketone S18 instead of S1 give the fully methylated dienophile S19, which failed to undergo clean cycloaddition with S15. This demonstrated that a H-bonded ortho OH substituent on the chalcone was critical for the success of the [4 + 2]-cycloaddition. Subsequent detailed studies including a computational investigation showed the acceleration of the cycloaddition reaction by the OH group arises both from the LUMO-lowering effect of the OH-carbonyl hydrogen bond and from better coplanarity between the diene and its aryl substituent in the transition structures [188]. Based on the Rizzacasa group's research, the subsequent synthesis of all chalcone dienophiles retained the presence of the free phenol in its C-2 position.

Enantioselective total syntheses of kuwanon X, kuwanon Y, and kuwanol A
In 2014, the Lei group developed a new strategy to forge the desired cyclohexene core unit of dehydroprenylchalcone type MDAAs. This new strategy featured an asymmetric Diels−Alder cycloaddition, catalyzed by a chiral ligand/boron Lewis acid to construct the core structure (see Sect. 4.3.4). In 2016, the same group adopted this strategy to construct the cyclohexene moiety of dehydroprenylstilbene type MDAAs. The biosynthesis-inspired asymmetric Diels − Alder cycloaddition shows high exo selectivity, in which the ratio of exo/endo could up to 13:1. The implementation of this strategy allowed for the first asymmetric total syntheses of the natural products kuwanons X and Y (58 and 61) and kuwanol A (64) in 12 and 11 steps, respectively [189]. The synthesis of dienes S28 (acetyl-protection) and S31 (MOM-protection) started with the preparation of S25 from methyl 3,5-dihydroxy-benzoate S20 in high yield over five steps including aromatic C-H iodination, TBS protection, DIBAL reduction, alkane C-OH iodination, and Michaelis-Arbuzov reaction (Scheme 3). The acetyl protected diene S28 was obtained over four steps by the Horner-Wadsworth-Emmons reaction of S25 with S26 followed by deprotection of the silyl protecting groups and reprotection with acetyl groups, and then via the Suzuki-Miyaura reaction. The authors found that an additional step of acetyl reprotection of the crude mixture produced by the Suzuki reaction could improve the yield of diene S28. In a branch procedure, precursors S25 and S26 were subjected to the same Horner-Wadsworth-Emmons reaction and deprotection conditions, and then reprotected with MOM groups to produce iodide S30, which performed the Heck reaction with 2-methyl-but-3-en-2-ol followed by dehydration to provide the desired MOM protected diene S31. The critical factor for the symmetric Diels − Alder cycloaddition between diene S28 and the known dienophile S32 was to find a suitable chiral ligand. After screening of chiral boron ligands for catalytic [4 + 2] cycloaddition, two chiral ligands (S)-VAPOL and (R)-6,6′-dibromo-VANOL could be used directly for the enantioselective total synthesis of acetyl ether precursors of 58 and 61, respectively, due to their very high exo-or endo-selectivity and ee value. As shown in Scheme 4, (S)-VAPOL effectively catalyzed the cycloaddition with high exo selectivity (exo/endo = 13:1) and ee value (97%), while the chiral ligand (R)-6,6′-dibromo-VANOL gave a good endo-selectivity (exo/endo = 3.5:1) and satisfying ee value (96%). Deacetylation of the corresponding exo-S33 and endo-S34 in the presence of K 2 CO 3 in the mixture of THF and MeOH furnished the natural products kuwanons X and Y (58 and 61), respectively. The biomimetic intramolecular ketalization of 58 and 61 was performed under the catalysis of sulfuric acid, but only 61 formed a ketalized product kuwanol A (64). The Lei group had further investigated whether the two acetyl groups near the dehydroprenyl group had obvious effect on the exo/endo stereoselectivity. As shown in Scheme 4, by using the MOM-protected diene S31 instead of the acetyl-protected diene S28 in the synthesis of kuwanol A (64) from the same dienophile S32 catalyzed by chiral (R)-VANOL-boron Lewis acid, the exo/endo stereoselectivity was changed from 5.3:1 to 1.2:1 without losing the enantioselectivity, but the total yield increased from 3.6% to 17.6% with one step shorter. Combined with other cases, the authors suggested that different substitutions in diene may contribute to different stereoselectivity in the asymmetric Diels − Alder cycloaddition.

Total syntheses of ( ±)-kuwanol E and ( ±)-kuwanon Y heptamethyl ether
Also in 2016, Iovine and coworkers completed their total syntheses of ( ±)-kuwanol E (62) and ( ±)-kuwanon Y heptamethyl ether (61a) via a convergent strategy in nine steps. The synthesis featured a Lewis acid-mediated biomimetic intermolecular Diels−Alder cycloaddition for creating a cyclohexene core unit from dienophiles S3 or S5 and dehydroprenylstilbene diene S46. Another key point in this synthesis was that its exo/endo diastereoselectivity was controlled by the reaction temperature [190]. The synthesis commenced with the preparation of dienophile S5 over several classical reported reactions involving Claisen-Schmidt condensation, prenylation, and sigmatropic rearrangement (Scheme 5). Different from the previous report, the use of montmorillonite K10 as the catalyst in [1,3]-rearrangement could improve the yield of S5. As depicted in Scheme 5, the synthetic route towards the key intermediate S46 started with commercially available 4-bromo-3,5-dihydroxybenzoic acid S36, which proceeded via Fischer esterification and methyl protection to obtain bromide S38. For exploring the effects of different halogen atoms (Br or I) on the subsequent reactions, iodide S39 was obtained by aromatic Finkelstein iodination of bromide S38. Next, compounds S38 or S39 were reduced with LiAlH 4 , and then converted into benzyl bromides S42 or S43 using PBr 3 , which exhibited different yields over the two steps. The one-pot Arbuzov and Horner − Wadsworth − Emmons reactions of S42 or S43 with S2 were performed to install the stilbene halides S44 or S45, in which their yields differed by more than one time. After Suzuki − Miyaura coupling of S44 or S45 with boronate S14, diene S46 was obtained in equivalent yield from the two building blocks, respectively. Therefore, the use of bromine substituted substrates in these reactions would give a better combined yield of diene S46. In addition, compared with traditional ligands such as PPh 3 or AsPh 3 , the use of S-Phos as a bulky and electron-rich ligand in this Suzuki−Miyaura coupling step was proved to be a key condition affecting the yield of the product.
The Diels − Alder cycloaddition of dienophile S5 and diene S46 in dry o-xylene with or without the catalyst BH 3 ·THF at various temperatures was performed, which exhibited different reactivity and diastereoselectivity. For example, at low temperatures (25 and 50 °C), the cycloaddition reaction had no reactivity, but as the temperature increased to 100 °C, a mixture of the exoand endo-adducts (S47 and S48) with a 1:4 ratio was obtained. However, when the temperature was further heated to 160 °C, it yielded S47 and S48 in the opposite ratio (4:1). Therefore, the production of the endo-isomers such as ( ±)-kuwanol E heptamethyl ether (S48) and ( ±)-kuwanon Y heptamethyl ether (61a) was carried out under the same conditions as shown in Scheme 5. Subsequently, ( ±)-kuwanol E (62) was obtained by demethylation of the corresponding endo-isomer S48 with BBr 3 in DCM. In this study, the cleavage of the methoxy groups of the heptamethyl ether precursor of ( ±)-kuwanon Y was not attempted due to its unavailable as well as because of the completed total synthesis of kuwanon Y by Lei group.

Total syntheses of ( ±)-kuwanon I heptamethyl ether and ( ±)-kuwanon J heptamethyl ether
In the studies of H-bond accelerated Diels-Alder cycloadditions of chalcones, in 2012 the Rizzacasa group had also completed the total syntheses of two heptamethyl ethers of the dehydroprenylchalcone type MDAAs to examine the cycloaddition reaction [188]. As shown in Scheme 7, the synthesis of the diene S61 started with the conversion of ketone S1 to iodide S59, which was then subjected to Claisen-Schmidt condensation with aldehyde S2 followed by methylation to afford a fully esterified chalcone S60. The subsequent Suzuki coupling with boronate S14 gave diene S61 in low yield, which underwent the [4 + 2]-cycloaddition reaction with the prepared dienophile S5 only to afford kuwanon I heptamethyl ether (78a) and the endo-isomer kuwanon J heptamethyl ether (81a) in a 1:1 ratio without the product resulting from the Diels-Alder reaction of diene S61 with itself as the dienophile. This result was also a proof to the importance of the H-bond in chalcone dienophile.
Brosimones A and B were homodimers derived from prenyl chalcone. Therefore, the synthesis started with the easily prepared acetophone S62 that underwent a two-step procedure to yield the benzyl-protected prenyl chalcone S65 (Scheme 8). Based on the model reaction established by the authors, the cycloadducts exo-S67 and endo-S66 with a ratio of 1.2:1 were obtained in 64% yield by dehydrogenative Diels-Alder cycloaddition/dimerization of S65 using the optimized Pt/C-AgNP conditions with cyclopentene as H 2 scavenger. Next, hydrogenolysis of exo-S67 produced ( +)-brosimone B (77), whose structure was confirmed by X-ray crystal analysis of its methyl-protected derivative S68 produced by methylation using Me 2 SO 4 . As shown in Scheme 8, the precursor exo-exo S69 of brosimone A also could be accessed by dehydrogenative cycloaddition of exo-S67 under different conditions including changing the temperature. For example, in the presence of DDQ and AgNPs as catalyst in chlorobenzene (PhCl) solvent, exo-S67 was converted into the cycloadduct exo-endo-S71 (17% yield) and the DDQ adduct S72 (34% yield) at 90 °C. Both exo-endo-S71 and DDQ adduct S72 could be converted exclusively into exo-exo S69 under AgNP-promoted conditions at 130 °C in excellent yield. When the reaction temperature was increased to 130 °C, the dehydrogenative Diels-Alder cycloaddition of exo-S67 predominantly afforded exo-exo S69 in 62% yield in the presence of AgNPs. Finally, the hydrogenolysis product of exo-exo S69 was determined to be ( +)-brosimone A (80) on the basis of the X-ray structure of its methyl derivative S70.

Enantioselective biomimetic total syntheses of kuwanons I and J and brosimones A and B
In 2014, the Lei group reported the first enantioselective total syntheses of dehydroprenylchalcone type MDAAs kuwanon I (78), kuwanon J (81), brosimone A (80), and brosimone B (77) by a common intermediate based on a concise synthetic strategy. The key feature of the synthesis included a biosynthesis-inspired asymmetric Diels-Alder cycloaddition mediated by a chiral ligand/ boron Lewis acid. Another important progress involved regioselective Schenck ene reaction, reduction, and dehydration to realize a biomimetic dehydrogenation for generation of the required diene precursor. Furthermore, a remarkable process involved a tandem inter-/intramolecular asymmetric Diels-Alder cycloaddition of a diene with itself as the dienophile [193]. As shown in Scheme 9, base-mediated Claisen-Schmidt condensation of the MOM-protected aldehyde S73 and ketone S74 readily produced 2' hydroxychalcone S75. The subsequent prenylation and sigmatropic rearrangement resulted in the formation of two isomers, para-and ortho-prenylated chalcones (S77 and S78). Next, the acetyl-protected dienophile S79 was obtained from the para-prenylated chalcone S77 in 33% yield by replacing MOM groups with acyl groups. After a brief optimization, the key visible-light-mediated regioselective Schenck ene reaction of S79 by using TPP as photosensitizer and MeOH as solvent occurred smoothly to deliver the tertiary allylic alcohol S80 and secondary allylic alcohol (not shown in Scheme 9) in 3.2:1 ratio. Then dehydration of S80 with SOCl 2 /DBU produced the diene or dienophile S81 in 68% yield. In a parallel procedure, deprotection of the MOM groups followed by reprotection of the ortho-isomer S78 with acetyl groups delivered the required dienophile triacetate S82 in 35% yield. Next, the visible-light-mediated regioselective Schenck ene reaction of S82 using Ru(bpy) 3 Cl 2 ·6H 2 O and MeOH gave an excellent ratio for the tertiary alcohol S84, a better substrate for dehydration, which smoothly provided the diene S85 under SOCl 2 /DBU in 75% yield.
With dienophiles S79, S81, and S82 and dienes S81 and S85 in hand, a series of asymmetric Diels-Alder reactions promoted by different ligand/boron Lewis acid for the synthesis of the target dehydroprenylchalcone type MDAAs were investigated. As depicted in Scheme 10, the preferred (S)-VANOL ligand catalyzed the cycloaddition of S79 and S85 to afford the exo-and endo-adducts (S86 and S87 with a 1:1.2 ratio) in 71% combined yield with excellent ee values for both. Similarly, the using of (S)-8,8'-dimethyl-VANOL was proved to be the best chiral ligand to obtain both exo-S88 and endo-S89 with good ee values. Final deprotection of the acetyl groups of exo-S86, exo-S87, and endo-S89 with K 2 CO 3 as a base efficiently furnished the desired natural products brosimone B (77), kuwanon I (78), and kuwanon J (81), respectively, each in 70% yield.
It is worth mentioning that a one-pot inter-/intramolecular Diels-Alder cycloaddition cascade was smoothly occurred to afford the three expected products including exo,exo-S90 in 13% yield, endo,endo-S91 in 28%, and exo,endo-S92 in 20% yield under the condition of a small amount of excess (S)-VANOL ligand (Scheme 11). Next, deprotection of exo,exo-S90 under mild basic conditions efficiently gave the target natural product brosimone A (80) in 70% yield. In addition, after removing the acetyl groups of S91 and S92 followed by methylation, S94 and S96 with definite structures were obtained over two steps, respectively.

Total syntheses of kuwanons G and H
In 2021, the Tang group reported a convergent route towards the total synthesis of two MDAAs named kuwanons G and H (92 and 93) with unique dehydroprenylflavone dienes. The key features of this approach included the use of Baker-Venkataraman rearrangement, alkylation of β-diketone, intramolecular cyclization, and Suzuki-Miyaura coupling to achieve the unstable dehydroprenylflavone diene [194].
As outlined in Scheme 12, the synthesis of the key intermediate diene S107 started with a selective methyl protection of 2′,4′,6′-trihydroxyacetophenone (S97). The addition of two methyls onto the acetophenone S97 was performed using (CH 3 O) 2 SO 2 in acetone to give S98. The following regioselective iodination of S98 resulted in the formation of iodobenzene S99 in 92% yield. After acylation of S100 with thionyl chloride, the crude product benzoyl chloride S101 was directly conducted with S99 to form an acyloxy ketone, which was then converted into β-diketone S102 through a base-catalyzed Baker-Venkataraman rearrangement. Next, alkylation of β-diketone S102 with prenyl bromide gave the desired S104 and by-product S103, and the later could be effectively hydrolyzed to the former. The treatment of S104 with concentrated sulfuric acid in anhydrous ethanol enabled intramolecular cyclization onto the target cyclic product S106 in 42% yield as well as an ethylated byproduct S105, which also could be further converted to S106 under acidic condition. With the aim of installing the diene moiety at C-8, the iodoflavonoid S106 was subjected to the Suzuki-Miyaura coupling reaction with the easily prepared S14 to dehydroprenylflavone diene S107 in 41% yield. The chalcone dienophiles S3 and S5 were easily furnished by the established route. As shown in Scheme 12, thermal-mediated intramolecular Diels-Alder cycloaddition of diene (S107) and dienophiles (S3 and S5) in a sealed tube with toluene smoothly occurred to the endo-and exo-adducts with a ratio of 1:1. Deprotection of the corresponding exo-isomers ( ±)-kuwanon G heptamethyl ether (S110) and ( ±)-kuwanon H heptamethyl ether (S111) finally yielded ( ±)-kuwanons G (92) and H (93), respectively, which were separated by a chiral HPLC to obtain the two natural products (-)-kuwanon G and (-)-kuwanon H.

Asymmetric total syntheses of sanggenons C and O
In 2016, the Porco group completed the asymmetric total syntheses of sanggenons C and O (130 and 131). The syntheses relied on a Lewis acid-promoted double Claisen rearrangement of a bis-allyloxyflavone to install the hydrobenzofuro[3,2-b]chromenone core structure of sanggenonflavone diene precursors, and a stereodivergent reaction of a racemic mixture (stereodivergent RRM) involving the B(OPh) 3  enantioselective [4 + 2] cycloaddition to furnish the target molecules [195]. The synthesis of the diene precursor S120 started with tetra-MOM group protection of the commercially available morin S112 (Scheme 13). Subsequent 5-allylation of the MOM-protected flavonoid S113 to afford the intermediate S114, which was transformed to S115 by a chemoselective deprotection of the 3-MOM group using NaI and a catalytic amount of aqueous HCl. After allylation of the C-3 free hydroxyl group of S115, the obtained product S116 was subjected to global deprotection to afford the desired bis-allyloxyflavone S117. After evaluation of a number of rare earth metal triflates for double rearrangement, it was found that Yb(OTf ) 3 , in the presence of CH 2 Cl 2 /HFIP (4:1), was used for producing the desired hydrobenzofuro[3,2-b]chromenone core structure S118 in 72% yield. With S118 in hand, the authors carried out silylation and crossmetathesis to afford the tri-silyl-protected ( ±)-sanggenol F [( ±)-S119] in excellent yield. The prenyl product ( ±)-S119 was then treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in tetrahydrofuran (THF) to transform to chromene ( ±)-S120 in 73% yield.

/BINOL complexes catalytic
The Porco group had applied two different strategies to construct the cyclohexene core unit. First, AgNPs-mediated intermolecular Diels-Alder cycloaddition of the TBS-protected diene precursor ( ±)-S120 with acetylated 2′-hydroxychalcone S32 smoothly occurred to yield a mixture of two endo cycloadducts and minimal production of exo diastereomers. The mixture of endo cycloadducts was sequentially treated with aqueous NaHCO 3 and NEt 3 ·3HF to yield a mixture of ( ±)-sanggenon C (130) and ( ±)-sanggenon O (131) in 36% combined yield over three steps. Next, in order to synthesize enantioenriched sanggenons C and O, a verified catalytic system to a stereodivergent RRM strategy was applied. Based on the model reaction, the asymmetric [4 + 2] cycloaddition of diene precursor ( ±)-S120 with dienophile S32 using B(OPh) 3 / (R)-BINOL as catalyst was carried out under the conditions of PhCF 3 . After sequential deprotection of both acetate and silyl protecting groups, the promising enantioselectivities sanggenon C (130, with 98% ee) and sanggenon O (131, with 93% ee) were obtained in 2:1 ratio.

Total syntheses of palodesangren B trimethyl ether and palodesangren D dimethyl ether
In 2019, the Ploypradith group reported the diastereoconvergent total synthesis of the palodesangrens B and D methyl ethers (139a and 141a), which were completed by installing the final 2H-pyran-2-one ring onto the tricyclic 9-methyl-6,7-diphenyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromene core constructed from appropriate chalcones and dienes. At the early stage of the synthetic route, the Diels-Alder reaction was utilized to assemble the cyclohexene moiety of the tricyclic core. Next, a novel diastereoconvergent LiAlH 4 -mediated isomerization of the mixture of exo-and endo-adducts to install the desired stereochemistry, and subsequent acid-mediated stereoselective cyclization was employed to set up the pyran ring. Finally, the formation of its 2H-pyran-2-one ring was achieved by four consecutive steps including the regioselective MgCl 2 -mediated Casnati−Skattebøl ortho-formylation of phenol, Wittig methylenation, acryloylation, and Ru(II)-catalyzed ringclosing metathesis. Overall, palodesangrens D dimethyl ether and B trimethyl ether were successfully obtained for the first time via this strategy over nine steps starting from the Diels−Alder reactions [196]. The synthesis commenced with the preparation of aryldiene S123 from bis-MOM-protected benzaldehyde S121 by the Claisen − Schmidt condensation and subsequent Wittig methylenation (Scheme 14). With diene S123 and known chalcone dienophile S124 in hand, their intermolecular Diels-Alder cycloaddition gave the corresponding cyclohexene S126 as a mixture of exo-and endo-adducts with a ratio of 1:1.4 in 63% yield. Subsequent acetyl group deprotection with LiAlH 4 followed by methylation with MeI provided S128 in 89% yield over two steps. The ensuing LiAlH 4 -mediated isomerization of the exo-and endo-adducts mixture S128 afforded a single endo isomer, which was directly subjected to acid-mediated chroman cyclization to furnish the desired tricyclic core S130 in 63% yield over two steps. After a brief optimization of the Casnati−Skattebøl reaction conditions, the key ortho-formylation of S130 proceeded smoothly to deliver the desired S132 in 46% yield and a small amount of the byproduct S134 (9%) together with 29% recovery of S130. Next, Wittig methylenation of S132 with MePPh 3 Br occurred smoothly in the presence of LiHMDS, and the resultant styrene S136 was subjected to acryloylation to provide the styrene acrylate S138. Finally, ring-closing metathesis of compound S138 using Grubbs II as the catalyst in toluene led to the formation of the desired palodesangren D dimethyl ether (141a). Similarly, palodesangren B trimethyl ether (139a) could be readily synthesized from aryldiene S123 and known chalcone dienophile S125 by using the same reaction sequences as 141a. The relative configurations of 139a and 141a were the same as those of natrual MDAAs palodesangrens B and D (139 and 141). In 2012, the Porco group developed a concise route towards the total synthesis of ( ±)-sorocenol B (149). This synthesis featured a silver nanoparticle (AgNP)-catalyzed Diels−Alder cycloaddition to form the cyclohexene core unit and a late-stage Pd(II)-catalyzed oxidative cyclization to install the requisite bicyclo[3.3.1] framework of sorocenol B [197].
The synthesis started with the preparation of chalcone S141 from the Claisen−Schmidt condensation between chromene S140 and benzaldehyde S73 with NaH as a preferred base in THF (Scheme 15). A hydrolysis of the MOM-protected S141 delivered a polyphenol, which then gave the acetyl-protected dienophile S142 under the presence of acetic anhydride. Next, the requisite diene S147 was prepared in four steps from resorcinol S143. After protection of S143 with MOMCl, the resulting MOM-ether S144 was subjected to a regioselective formylation to afford benzaldehyde S145 in 83% yield over two steps. Sequential a base-catalyzed aldol condensation of S145 with acetone followed by the Wittig olefination yielded the desired diene S147. The key Diels−Alder cycloaddition between dienophile S142 and diene S147 was then implemented by utilizing silica-supported silver nanoparticles (AgNP's), which efficiently allowed the formation of the desired cycloadducts exo-S148 and endo-S149 in 90% combined yield with a 1:2 ratio of exo/endo diastereomers. By unmasking the acetyl-protected phenols of S149, the obtained S150 was submitted to an oxidative Wacker cyclization catalyzed by Pd(OAc) 2 to construct the bicyclo [1,3,3] product. As a result, the desired S151 and its C-4 epimer S152 were produced with a ratio of 2:1 in 50% combined yield (Scheme 15). The total synthesis of ( ±)-sorocenol B (149) was fulfilled after hydrolysis of S151 using aqueous HCl in MeOH.